CN1321986C - Method for preparing 4,6 dichloropyridine - Google Patents
Method for preparing 4,6 dichloropyridine Download PDFInfo
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- CN1321986C CN1321986C CNB2005100772421A CN200510077242A CN1321986C CN 1321986 C CN1321986 C CN 1321986C CN B2005100772421 A CNB2005100772421 A CN B2005100772421A CN 200510077242 A CN200510077242 A CN 200510077242A CN 1321986 C CN1321986 C CN 1321986C
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- trichloromethylchloroformate
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Abstract
The present invention relates to a method for preparing 4, 6-dichloropyridine. With the existence of suitable alkali and a certain amount of solvent or mixed solvent, diphosgene or triphosgene chlorinates 4, 6-dihydroxy pyrimidine, which generates 4, 6-dichloropyridine. The purpose of the present invention is to provide a method for preparing 4, 6-dichloropyridine, which has the advantages that the operation is simple and convenient, and the method is suitable for industrialization.
Description
Technical field
The present invention relates to use trichloromethylchloroformate or triphosgene, in the presence of suitable alkali, with 4, the 6-dihydroxy-pyrimidine is converted into 4, the method for 6-dichloro pyrimidine.4, the 6-dichloro pyrimidine can be used as the chemical intermediate of agricultural chemicals and medicine industry, as can be used for preparing sterilant Azoxystrobin, nucleoside analog and at activated compound of central nervous system (CNS) etc.
Background technology
Because 4, the 6-dichloro pyrimidine is purposes and importance economically widely, many synthesizing chlorinated pyrimidines particularly 4, the method for 6-dichloro pyrimidine has obtained exploitation.
WO02/04428 (Chinese patent 01812416.X) has disclosed and has a kind ofly generated the imido acyl chloride compound by organic amide (as methane amide, ethanamide) and phosgene or by organic nitrile (as butyronitrile) and hcl reaction, the imido acyl chloride compound generates 4 with phosgene reaction subsequently, the preparation method of 6-dichloro pyrimidine.But this patent does not provide its result data (yield, content etc.).This method has big distance apart from industrialization.
Therefore by 4, the 6-dihydroxy-pyrimidine carries out chlorination reaction and generates 4, and the 6-dichloro pyrimidine is still the preparation method who generally adopts at present.
Relate generally in the presence of suitable alkali, by 4,6-dihydroxy-pyrimidine and phosphoryl chloride prepared in reaction 4, the method for 6-dichloro pyrimidine comprise Kenner etc. (J.CHEM.SOC., Nov.1943, pp574-575); Hull (J.CHEM.SOC., Aug.1951, p2214); English Patent GB2287466; United States Patent (USP) 5,583,226,5,723,612,6,018,045 etc.When the problem of these methods is to use on a large scale, produce quite a large amount of phosphoric acid by products, these by products must be disposed in a certain way.
The United States Patent (USP) 5,677,453 (Chinese patent 96109338.2) of Cramm etc. has proposed by 4, and 6-dihydroxy-pyrimidine and the reaction of excessive phosphoryl chloride are synthetic 4, the method for 6-dichloro pyrimidine.In this synthetic method, do not add alkali, but adopt excessive phosphorus and muriate (with respect to 4, the 6-dihydroxy-pyrimidine) to keep phosphorus trichloride to be in excess in chlorine in the reaction mixture by phosphorus trichloride and chlorine are added to.Yet this method need distill out large numbers of excessive phosphorus trichlorides and phosphoryl chloride at last, product 4, and the 6-dichloro pyrimidine also will be separated by distillation, therefore uses this method that bigger energy consumption problem is arranged.
WO95/29166 such as Jones (United States Patent (USP) 5,750,694; 6-dihydroxy-pyrimidine and phosgene reaction preparation 4, the method for 6-dichloro pyrimidine are disclosed in the presence of suitable alkali by 4 Chinese patent 20031012068.7).Suitable alkali comprises tertiary amine and heterocyclic amine, and the molar ratio range of preferred bases and phosgene is 1: 10 to 10: 1.Preferred this is reflected in a kind of solvent or the mixed solvent and carries out.But, be that some height of the relevant phosgene transportation that produces therefrom, storage, use aspect are restrictive, the safety rule system of legislation on the other hand, thereby the use of this method is subjected to bigger restriction on the one hand because phosgene toxicity height.
Summary of the invention
The object of the present invention is to provide a kind of easy and simple to handle, be suitable for industrialized 4, the preparation method of 6-dichloro pyrimidine.Of the present invention 4, the preparation method of 6-dichloro pyrimidine is in the presence of suitable alkali, with trichloromethylchloroformate or triphosgene processing 4,6-dihydroxy-pyrimidine.The trichloromethylchloroformate (superpalite) and the crystalline triphosgene (two (trichloromethyl) carbonic ether) that under the standard state are liquid are the stable phosgene substitutes.Under the condition that certain catalyzer exists, trichloromethylchloroformate and triphosgene can be converted into phosgene quantitatively.
4, the 6-dihydroxy-pyrimidine also can tautomeric forms exist, and comprises its all tautomeric forms.
Trichloromethylchloroformate and triphosgene are the phosgene substitutes of safety and stability, are convenient to store, transport and use.Have found that trichloromethylchloroformate or triphosgene can replace phosgene to finish chlorination 4, the 6-dihydroxy-pyrimidine generates 4, the reaction of 6-dichloro pyrimidine, and need be with the usage quantity (with respect to 4, the 6-dihydroxy-pyrimidine) of excessive several times.Triphosgene is used in special recommendation of the present invention, on the one hand because its better security can provide better yield and higher product purity owing to it on the other hand.Certainly using trichloromethylchloroformate to finish this reaction also is that right of the present invention is desired.
Suitable alkali is tertiary amine and heterocyclic amine.Tertiary amine comprises triethylamine, N, and accelerine, N, N-diisopropylethylamine, heterocyclic amine comprise pyridine, 2-picoline, 4-picoline, imidazoles and N-crassitude.Preferred triethylamine and pyridine.
Present method is preferably carried out in solvent or mixed solvent.Solvent can be aprotonic solvent, for example normal hexane, toluene, dimethylbenzene etc.; Chlorinated solvent is methylene dichloride, chloroform, 1 for example, 2-ethylene dichloride, chlorobenzene etc.Mixed solvent comprises the double solvents of being made up of above-mentioned two or more solvents, for example the mixture of normal hexane and ethylene dichloride.
The usage quantity of triphosgene is in present method: triphosgene: 4, and 6-dihydroxy-pyrimidine=2/3: 1 to 2: 1 (mol ratio), preferred 2/3: 1 to 1: 1.The usage quantity of trichloromethylchloroformate is: trichloromethylchloroformate: 4, and 6-dihydroxy-pyrimidine=1: 1 to 3: 1 (mol ratio), preferred 1: 1 to 2: 1.The usage quantity of alkali is in present method: alkali: triphosgene=1: 1 to 7: 1 (mol ratio), preferred 1: 1 to 3: 1; Or alkali: trichloromethylchloroformate=0.5: 1 to 5: 1 (mol ratio), preferred 0.5: 1 to 2: 1.Therefore their threes' ratio is preferred 4, and 6-dihydroxy-pyrimidine: suitable alkali: the mol ratio of triphosgene is 1: (2/3～3): (2/3～1); Or 4,6-dihydroxy-pyrimidine: suitable alkali: the mol ratio of trichloromethylchloroformate is 1: (0.5～4): (1～2).
Present method is preferably carried out in-20 ℃～120 ℃ temperature ranges, and especially 0～100 ℃, particularly 0～70 ℃.Reactant should place ice bath before heating.
Of the present invention in the presence of suitable alkali, with trichloromethylchloroformate or triphosgene chlorination 4, the 6-dihydroxy-pyrimidine generates 4, the method of 6-dichloro pyrimidine comprises trichloromethylchloroformate or triphosgene is added to 4, in the mixture of 6-dihydroxy-pyrimidine and alkali, also comprise alkali is added to 4, in the mixture of 6-dihydroxy-pyrimidine and trichloromethylchloroformate or triphosgene.The present invention can provide more than 85%, usually is to surpass 90% yield.
Embodiment
The following example is used to illustrate the present invention, but is not limited in the scope of illustrating in the claim.In the following example used plant and instrument with preceding should be dry, reaction will be carried out under anhydrous condition.
Embodiment 1
Imposing ice bath, stirring under the good condition, to 4,6-dihydroxy-pyrimidine (34.2g, 0.3mol) and triphosgene (90g, 0.3mol) in the mixture of ethylene dichloride (400ml), be added dropwise to triethylamine (126ml, 0.9mol) and the immiscible material of ethylene dichloride (150ml), temperature control is adding more than 30 minutes below 5 ℃.With the mixture of gained restir below 5 ℃ 30 minutes.Remove ice bath and at room temperature stirred 1 hour, and then stirred 2 hours at 60 ℃.The cooling reactant, then water (3 * 300ml) washings, water layer use again ethylene dichloride (2 * 100ml) extractions merge organic extract liquid, water (200ml) washing again, anhydrous magnesium sulfate drying, the precipitation drying obtains 4,6-dichloro pyrimidine solid crystal 42.3g.It is 99% that HPLC analyzes content, and productive rate is corresponding to 93.6% of theory.
Embodiment 2
Imposing ice bath, stirring under the good condition, to 4,6-dihydroxy-pyrimidine (34.2g, 0.3mol) and trichloromethylchloroformate (81g, 0.4mol) in the mixture of ethylene dichloride (400ml), be added dropwise to triethylamine (112ml, 0.8mol) and the immiscible material of ethylene dichloride (150ml), temperature control is adding more than 1 hour below 5 ℃.With the mixture of gained restir below 5 ℃ 30 minutes.Remove ice bath and at room temperature stirred 1 hour, and then stirred 1 hour, stirred 1 hour at 70 ℃ at 50 ℃.The cooling reactant, then water (3 * 300ml) washings, water layer use again ethylene dichloride (2 * 100ml) extractions merge organic extract liquid, water (200ml) washing again, anhydrous magnesium sulfate drying, the precipitation drying obtains 4,6-dichloro pyrimidine solid crystal 41.3g.It is 98% that HPLC analyzes content, and productive rate is corresponding to 90.7% of theory.
Embodiment 3
Imposing ice bath, stirring under the good condition, to 4,6-dihydroxy-pyrimidine (34.2g, 0.3mol) and triethylamine (126ml, 0.9mol) in the mixture of ethylene dichloride (250ml), be added dropwise to the triphosgene that is dissolved in the ethylene dichloride (300ml) (90g, 0.3mol), temperature control is adding more than 30 minutes below 5 ℃.With the mixture of gained restir below 5 ℃ 30 minutes.Remove ice bath and at room temperature stirred 1 hour, and then stirred 2 hours at 60 ℃.As described in embodiment 1, handle, obtain 4,6-dichloro pyrimidine solid crystal 42.7g.It is 99% that HPLC analyzes content, and productive rate is corresponding to 94.5% of theory.
Embodiment 4
Imposing ice bath, stirring under the good condition, to 4,6-dihydroxy-pyrimidine (34.2g, 0.3mol) and pyridine (73.5ml, 0.9mol) in the mixture of ethylene dichloride (250ml), be added dropwise to the triphosgene that is dissolved in the ethylene dichloride (300ml) (90g, 0.3mol), temperature control is adding more than 30 minutes below 5 ℃.With the mixture of gained restir below 5 ℃ 30 minutes.Remove ice bath and at room temperature stirred 1 hour, and then stirred 2 hours at 60 ℃.As described in embodiment 1, handle, obtain 4,6-dichloro pyrimidine solid crystal 42.0g.It is 99% that HPLC analyzes content, and productive rate is corresponding to 93.0% of theory.
Embodiment 5
Imposing ice bath, stirring under the good condition, to 4,6-dihydroxy-pyrimidine (34.2g, 0.3mol) and triethylamine (126ml, 0.9mol) in the mixture of normal hexane (250ml), be added dropwise to the triphosgene that is dissolved in the normal hexane (300ml) (90g, 0.3mol), temperature control is adding more than 30 minutes below 5 ℃.With the mixture of gained restir below 5 ℃ 30 minutes.Remove ice bath and at room temperature stirred 1 hour, and then stirred 2 hours at 60 ℃.The cooling reactant, then water (3 * 300ml) washings, water layer use again normal hexane (2 * 100ml) extractions merge organic extract liquid, water (200ml) washing again, anhydrous magnesium sulfate drying, the precipitation drying obtains 4,6-dichloro pyrimidine solid crystal 41.7g.It is 99% that HPLC analyzes content, and productive rate is corresponding to 92.5% of theory.
Claims (6)
1, a kind of preparation 4, the method for 6-dichloro pyrimidine is characterized in that in the presence of alkali, handles 4, the 6-dihydroxy-pyrimidine with trichloromethylchloroformate or triphosgene; The mol ratio usage quantity of triphosgene is: triphosgene: 4, and 6-dihydroxy-pyrimidine=2/3: 1 to 2: 1; The mol ratio usage quantity of trichloromethylchloroformate is: trichloromethylchloroformate: 4, and 6-dihydroxy-pyrimidine=1: 1 to 3: 1; The mol ratio usage quantity of alkali is: alkali: triphosgene=1: 1 to 7: 1, alkali: trichloromethylchloroformate=0.5: 1 to 5: 1; Be reflected in solvent or the mixed solvent and carry out; Be reflected in-20 ℃～120 ℃ temperature ranges and carry out, reactant should place ice bath before heating;
Above-mentioned alkali is tertiary amine and heterocyclic amine, and tertiary amine is selected from triethylamine, N, accelerine or N, N-diisopropylethylamine; Heterocyclic amine is selected from pyridine, 2-picoline, 4-picoline, imidazoles or N-crassitude;
Above-mentioned solvent is aprotonic solvent or chlorinated solvent, and aprotonic solvent is selected from normal hexane, toluene or dimethylbenzene; Chlorinated solvent is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride or chlorobenzene; The double solvents that so-called mixed solvent is made up of above-mentioned multiple solvent.
2. according to the method for claim 1, it is characterized in that the mol ratio usage quantity of triphosgene is: triphosgene: 4,6-dihydroxy-pyrimidine=2/3: 1 to 1: 1; The mol ratio usage quantity of trichloromethylchloroformate is: trichloromethylchloroformate: 4, and 6-dihydroxy-pyrimidine=1: 1 to 2: 1.
3. according to the method for claim 1, it is characterized in that the mol ratio usage quantity of described alkali is: alkali: triphosgene=1: 1 to 3: 1; Alkali: trichloromethylchloroformate=0.5: 1 to 2: 1.
4. according to the method for claim 1, it is characterized in that trichloromethylchloroformate or triphosgene are added to 4, in the mixture of 6-dihydroxy-pyrimidine and alkali, or alkali is added to 4, in the mixture of 6-dihydroxy-pyrimidine and trichloromethylchloroformate or triphosgene.
5. according to the method for claim 1, it is characterized in that being reflected in 0～100 ℃ of temperature range and carry out.
6. according to the method for claim 1, it is characterized in that being reflected in 0～70 ℃ of temperature range and carry out.
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| CNB2005100772421A CN1321986C (en) | 2005-06-20 | 2005-06-20 | Method for preparing 4,6 dichloropyridine |
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| CNB2005100772421A CN1321986C (en) | 2005-06-20 | 2005-06-20 | Method for preparing 4,6 dichloropyridine |
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| CN1321986C true CN1321986C (en) | 2007-06-20 |
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| CN101898925B (en) * | 2009-05-27 | 2013-10-02 | 韶远化学科技（上海）有限公司 | Green synthesis and industrialization method of chloro-substituted heterocyclic ring |
| CN102070536A (en) * | 2011-02-14 | 2011-05-25 | 符爱清 | Method for preparing 2,4-dichloro-5-fluoropyrimidine compound |
| CN104211648A (en) * | 2014-08-25 | 2014-12-17 | 天津市中央药业有限公司 | Synthetic process method of erlotinib intermediate |
| CN105439963B (en) * | 2016-01-29 | 2018-02-02 | 河南中医学院 | The method that 4,6 dichloro pyrimidines are prepared under sulfuric acid catalysis |
| CN105859636A (en) * | 2016-05-13 | 2016-08-17 | 安徽广信农化股份有限公司 | Synthesis method of 4,6-dichloropyrimidine with 4,6-dihydroxypyrimidine serving as midbody |
| CN105906570A (en) * | 2016-05-13 | 2016-08-31 | 安徽广信农化股份有限公司 | Synthesis technology of 4,6-dichloropyrimidine |
| CN105859637A (en) * | 2016-05-13 | 2016-08-17 | 安徽广信农化股份有限公司 | Synthesis of 4,6-dichloropyrimidine and process optimization |
| CN106053691A (en) * | 2016-07-19 | 2016-10-26 | 安徽广信农化股份有限公司 | Method for measuring content of 4,6-dichloropyrimidine |
| CN106045917A (en) * | 2016-07-19 | 2016-10-26 | 安徽广信农化股份有限公司 | Synthetic process for preparing 4,6-dichloropyrimidine through one-step method |
| CN108341784A (en) * | 2017-01-24 | 2018-07-31 | 重庆紫光化工股份有限公司 | The synthetic method of 4,6- dichloro pyrimidines |
| CN109796413A (en) * | 2019-01-24 | 2019-05-24 | 安徽广信农化股份有限公司 | A kind of triethylamine recovery process for the synthesis of 4,6- dichloro pyrimidine |
| CN110204495A (en) * | 2019-06-03 | 2019-09-06 | 浙江工业大学 | A kind of preparation method of chloro polyhydroxy nitrogen heteroaromatic rings compound |
| CN114644591B (en) * | 2020-12-17 | 2023-12-29 | 北京颖泰嘉和生物科技股份有限公司 | Process for preparing dichloropyrimidine |
| CN113912550A (en) * | 2021-11-11 | 2022-01-11 | 浙江先锋科技股份有限公司 | Method for preparing 2,4, 5-trichloropyrimidine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5750694A (en) * | 1994-04-26 | 1998-05-12 | Zeneca Limited | Process for the preparation of 4,6-dichloropyrimidine |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5750694A (en) * | 1994-04-26 | 1998-05-12 | Zeneca Limited | Process for the preparation of 4,6-dichloropyrimidine |
Non-Patent Citations (3)
| Title |
|---|
| 三光气的合成及应用 王正平，刘天才，哈尔滨工程大学学报，第22卷第2期 2001 * |
| 甲酸甲酯氯化制双光气 周宾坤，天然气化工，第20卷第6期 1995 * |
| 甲酸甲酯氯化制双光气 周宾坤，天然气化工，第20卷第6期 1995;三光气的合成及应用 王正平，刘天才，哈尔滨工程大学学报，第22卷第2期 2001 * |
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